Antiparasitic artemisinin derivatives (endoperoxides)

ABSTRACT

This invention relates to certain novel C-10 substituted derivatives of artemisinin, a process for their preparation, their use in the treatnent and/or prophylaxis of diseases caused by infection with a parasite and pharmaceutical compositions containing such C-10 substituted derivatives.

This invention relates to certain novel C-10 substituted derivatives ofartemisinin, a process for their preparation, their use in the treatmentand/or prophylaxis of diseases caused by infection with a parasite andpharmaceutical compositions containing such C-10 substitutedderivatives.

Malaria is the most important human parasitic disease in the worldtoday. Approximately 270 million people throughout the world areinfected with malaria, with about 2 million dying each year. The abilityof parasites to produce a complex survival mechanism by expressingvariant antigens on the surface of infected erythrocytes makes itpossible for the parasites to escape from the destructive action of thehost immune response against these antigens. In addition, the increasingrate of malaria infection is due to the spread of chloroquine-resistantstrains of Plasmodium falciparum and the other multi-drug resistantstrains.

In the field of animal health, parasitic diseases are a major problem,especially those diseases which are functionally related to malaria. Forinstance, neosporosis is a term used to describe diseases caused byparasites of the species Neospora, especially Neospora caninum, inanimals. Neospora infections are known to occur in dogs, cattle, sheep,goats and horses.

The final host for Neospora spp., including Neospora caninum, is unknownand, in addition, the complete cycle of development of the parasite isnot understood. The asexual phases of reproduction, known as schizogony,and the behaviour of the unicellular tachyzoite/bradyzoite stage havebeen clarified, however. Tachyzoites are infectious unicellular parasitestages of about 3-7×1-5 mm in size formed after intracellularreproduction termed endodyogeny. Reproduction via tachyzoites takesplace preferentially in organelles such as muscle or nerve cells.Pathological symptoms invoked after an infection are associated mainlyin those tissues. Some five to six weeks after natural infection in adog, symptoms of the disease are hypersensitivity caused by inflammationof neuronal cells and increasing tendency to hyperextension of the hindlegs. Histopathological lesions are apparent in the nervous system,preferentially in the brain and spinal cord. Extensive non-suppurativeinflammations, glial excrescences and perivascular infiltrations ofmononuclear cells (macrophages, lymphocytes, plasma cells) dominate, andare also partly apparent in eosinophils and neutrophils. In the muscularsystem, macroscopically observable necroses and degenerative changesappear. Apart from the more or less strongly developed atrophy, longpale longitudinal stripes are evident.

In California and Australia, Neospora caninum infections appear to bethe main cause for abortion in cattle. Symptoms of the disease in cattleare similar to those in the dog. Ataxia is apparent, joint reflexes areweakened and pareses at the hind legs, partly in all four legs, can beobserved. The histological picture is similar to that of the dog; mainlynon-suppurative meningitis and myelitis.

Data on in vivo activity of compounds suitable against neosporosis arerare because adequate in vivo test systems still have to be developed.Sulfadiazin (administered via drinking water) is effective inexperimentally infected mice, only if the treatment was prophylactic,that is, the treatment was started before infection. In dogs, treatmentwith sulfadiazin and clindamycin is only successful if it is startedearly, that is, at the appearance of first clinical symptoms as a resultof neuronal inflammation.

Coccidiosis, an infection of the small intestine, is relatively rarelydiagnosed in humans, where it is caused by Isospora belli. However,humans are also the final host of at least two cyst-forming coccidialspecies (Sarcocystis suihominis and S. bovihomimis). Consumption of rawor inadequately cooked pork or beef containing such cysts can lead tosevere diarrhoea, the cause of which is probably seldom diagnosedcorrectly. Coccidia (phylum Apicomplexa, suborder Eimeriina) are one ofthe most successful groups of parasitic protozoans, having conqueredvirtually every class of Metazoa. The ones that are of particularimportance for man are the 60-100 species which parasitise domesticanimals and which in some instances can cause very severe losses,especially in poultry, although also in lambs, calves, piglets, rabbitsand other animals (see Table A). TABLE A Causatives of intestinalcoccidiosis in domestic animals number of Eimeria and/or most pathogenicand/or very Isospora common species Animal species*) (E = Eimeria, I =Isospora) chicken (Gallus gallus) 7 E. tenella, E. necatrix, E. maxima,E. acervulina turkey (Meleargidis 7 E. meleagrimitis, E. adenoidesgallopavo) goose (Anser anser) 6 E. anseris, E. truncata, E. nocens, E.kotlani duck (Anas 3 Tyzzeria perniciosa, E. anatis platyhynehus) pigeon(Columba livia) 2 E. columbarum, E. labbeanea rabbit (Oryctolagus 11(12) E. intestinalis, E. flavescens, cuniculus) E. stiedai, E. magna, E.perforans sheep (Ovis arius) 11 (16) E. ovinoidalis, E. ashata, E. ovinagoat (Capra hircus) 12 (15) E. ninakohlyakimovae, E. arloingi cattle(Bos taurus) 12 (15) E. zuernii, E. bovis, E. auburnensis pig (Susscofra)  7 (14) I. suis, E. debliecki, E. scabra dog (Canis familiaris)5 I. canis, I. (Cystisospora) burrowsi cat (Felis catus) 2 + 6 I. felis,I. rivolta as final host: Sarcocystis bovifelis, S. ovifelis, S.fusiformis, S. muris, S. cuniculi, Toxoplasma gondii*)regarding to Pellerdy (1974), Eckert et al, (1995b, Levine and Ivens(1970) and Mehlhorn 1988)

Most of the pathogenic species are strictly host-specific. They have acomplex life cycle with two asexual reproduction phases (schizogony ormerogony, and sporogony) and a sexual development phase (gametogony). Inview of the major importance of coccidiosis, numerous reviews areavailable, for instance, by Davies et al. (1963), Hammond and Long(1973), Long (1982, 1990), and Pellerdy (1974). The economicallyimportant species sometimes differ very considerably in theirsensitivity to medicinal active ingredients. The sensitivity of thedifferent developmental stages to medicinal agents also variesenormously.

As far as the use of drugs is concerned, prophylaxis is the mainapproach in poultry, in which symptoms do not appear until the phase ofincreased morbidity, and therapy is the principal strategy in mammals(McDougald 1982). Polyether antibiotics and sulfonamides, among otherdrugs, are currently used for such treatment and prophylaxis. However,drug-resistant strains of Eimeria have emerged and drug-resistance isnow a serious problem. New drugs are therefore urgently required. Giventhe multiplicity of pathogens and hosts, there is no “ideal model” foridentifying and testing anticoccidial agents. For example, most of themany substances used for preventing coccidiosis in poultry areinsufficiently effective or even completely ineffective againstmamrnalian coccidia (Haberkorn and Mundt; 1989; Haberkorn 1996).Numerous works and sets of instructions have been published on testingof active ingredients in animals for anticoccidial efficacy, forimmunisation, etc. One particularly important and comprehensive exampleis the survey of current methods published by Eckert et al. (1995a).

The compound artemisinin, also known as qinghaosu (1), is a tetracyclic1,2,4-trioxane occurring in Artemisia annua. Artemisinin and itsderivatives dihydroartemisinin (2), artemether (3) and sodium artesunate(4) have been used for the treatment of malaria.

Different modes of action have been proposed by various groups toaccount for the action of artemisinin and its derivatives in treatingmalaria (Posner et al., J. Am. Chem. Soc. 1996, 118, 3537,; Posner etal., J. Am. Chem. Soc. 1995, 117, 5885; Posner et al., J. Med. Chem.1995, 38, 2273). However, irrespective of actual mode of action, allcurrent derivatives suffer from poor oral bioavailability and poorstability (Meshnick et al., Parasitology Today 1996, 12, 79), especiallythe ‘first generation’ ethers and esters artemether and sodiumartesunate obtained from dihydroartemisinin. Extensive chemical studiescarried out on artemisinin and derivatives indicate that a cause ofinstability is the facile opening of the trioxane moiety in artemisininitself, or in the metabolite common to all currently used derivativesartemether, arteether and artesunate, namely dihydroartemisinin. Ringopening will provide the free hydroperoxide, which is susceptible toreduction. Removal of this group ensures destruction of drug activitywith the reduction products being transformed into desoxo metabolites.In order to render ring-opening less facile, the oxygen atom at C-10 canbe either removed to provide 10-deoxydihydroartemisinin, or replaced byother groups, and this has provided the basis for the so-called ‘secondgeneration’ compounds which are generally 10-deoxy artemisininderivatives. In addition, derivatives of artemisinin have also beenprepared with a variety of substituents at C-9.

Artemisinin derivatives are also known in which the oxygen atom at C-10has been replaced by an amine group. For instance, Yang et al (Biorg.Med. Chem. Lett., 1995, 5, 1791-1794) synthesised ten new artemisininderivatives in which the oxygen atom at C-10 was replaced by a group-NHAr where Ar represents a phenyl, 3-chlorophenyl, 4-chlorophenyl,3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylphenyl,4-methoxyphenyl, 3-carboxylphenyl or 4-carboxylphenyl group. Thesecompounds were tested for in vivo activity against the K173 strain ofPlasmodium berghei and found to be active.

WO 00/04024 discloses further C-10 substituted derivatives ofartemisinin.

Whilst the current artemisinin derivatives are successful, there areproblems associated with stability, bioavailability and potentialneurotoxicity. There is also a need for artemisinin derivatives whichexhibit a broad spectrum of activity against a variety of parasites.

It has now been discovered that certain C-10 substituted derivatives ofartemisinin are effective in the treatment of diseases caused byinfection with a parasite. These compounds are particularly effective inthe treatment of diseases caused by infection with a parasite of thegenera Plasmodium, Neospora or Eimeria, especially Plasmodiumfalciparum, Neospora caninum and Eimeria tenella which cause malaria,neosporosis and coccidiosis respectively.

According to the present invention there is therefore provided acompound of the general formula I

or a salt thereof, or a solvate thereof, or a solvate of a salt thereof,

-   -   in which    -   R¹ represents a hydrogen atom or an optionally substituted        alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group;    -   X represents a carbon atom, a sulfur atom, a sulfoxide group S═O        or a group PR³, P—O—R³ or P—N(R⁴)—R³ where R³ and R⁴ each        independently represent a hydrogen atom or an optionally        substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl        group;    -   Z represents an oxygen atom, a sulfur atom or a group NR⁵ where        R⁵ represents a hydrogen atom or an optionally substituted        alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group; and    -   R² represents a hydrogen atom or an optionally substituted        alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group, or a        group N(R⁶)₂, NHNH₂, NR⁶NHR⁶ or NR⁶N(R⁶)₂, or a group OR⁶ or SR⁶        where each R⁶ independently represents a hydrogen atom or an        optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl        or aralkyl group, or a 10α-dihydroartemisinyl group, or R²        represents a group OR⁷ or NR⁶R⁷ where R⁶ represents a group as        defined above and R⁷ represents a bond attached as a substituent        to R⁵ together with the interjacent group —X═Z— forming an        optionally substituted heterocyclic group where Z represents a        group NR⁵, or R⁷ represents a bond attached as a substituent to        R¹ together with the interjacent group —N—X(═Z)— forming an        optionally substituted heterocyclic group.

Suitable salts include acid addition salts and these may be formned byreaction of a suitable compound of formula I with a suitable acid, suchas an organic acid or a mineral acid. Acid addition salts formed byreaction with a mineral acid are particularly preferred, especiallysalts formed by reaction with hydrochloric or hydrobromic acid.

A solvate according to the present invention is any such form of thecompounds forming a complex in solid or liquid state by coordinationwith solvent molecules. Hydrates are a special form of solvates formedby coordination with water molecules.

Any alkyl, alkenyl or alkynyl group, unless otherwise specified, may belinear or branched and may contain up to 12, preferably up to 6, andespecially up to 4 carbon atoms. Preferred alkyl groups are methyl,ethyl, propyl and butyl. It is preferred that any alkenyl or alkynylgroup is not an alk-1-enyl or alk-1-ynyl group. In other words, thereshould preferably be at least one methylene group —CH₂— or similarsp³-hybridised center between a carbon atom forming part of the doubleor triple C—C bond and the nitrogen atom to which the group is attached.Preferred alkenyl and alkynyl groups include propenyl, butenyl, propynyland butynyl groups. When an alkyl moiety forms part of another group,for example the alkyl moiety of an aralkyl group, it is preferred thatit contains up to 6, especially up to 4, carbon atoms. Preferred alkylmoieties are methyl and ethyl.

An aryl group may be any aromatic hydrocarbon group and may contain from6 to 24, preferably 6 to 18, more preferably 6 to 16, and especially 6to 14, carbon atoms. Preferred aryl groups include phenyl, naphthyl,anthryl, phenanthryl and pyryl groups, especially a phenyl or naphthyl,and particularly a phenyl, group. When an aryl moiety forms part ofanother group, for example the aryl moiety of an aralkyl group, it ispreferred that it is a phenyl, naphthyl, anthryl, phenanthryl or pyryl,especially phenyl or naphthyl, and particularly a phenyl, moiety.

An aralkyl group may be any alkyl group substituted by an aryl group. Apreferred aralkyl group contains from 7 to 30, particularly 7 to 24 andespecially 7 to 18, carbon atoms, particularly preferred aralkyl groupsbeing benzyl, naphthylmethyl, anthrylmethyl, phenanthrylmethyl andpyrylmethyl groups. A particularly preferred aralkyl group is a benzylgroup.

A cycloalkyl group may be any saturated cyclic hydrocarbon group and maycontain from 3 to 12, preferably 3 to 8, and especially 3 to 6, carbonatoms. Preferred cycloalkyl groups are cyclopropyl, cyclopentyl andcyclohexyl groups.

A heteroaryl group may be any aromatic monocyclic or polycyclic ringsystem which contains at least one heteroatom. Preferably, a heteroarylgroup is a 5- to 18-membered, particularly a 5- to 14-membered, andespecially a 5- to 10-membered, aromatic ring system containing at leastone heteroatom selected from oxygen, sulphur and nitrogen atoms.Preferred heteroaryl groups include pyridyl, pyrylium, thiopyrylium,pyrrolyl, furyl, thienyl, indolinyl, isoindolinyl, indolizinyl,imidazolyl, pyridonyl, pyronyl, pyrimidinyl, pyrazinyl, oxazolyl,thiazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl,pyridazinyl, benzofuranyl, benzoxazolyl and acridinyl groups. A C-linkedheteroaryl group is therefore a heteroaryl group as defined above whichis linked to the tetracyclic 1,2,4-trioxane moiety of a compound ofgeneral formula I via a carbon atom in the heteroaromatic ring system.

A heterocyclic group may be any monocyclic or polycyclic ring systemwhich contains at least one heteroatom and may be unsaturated orpartially or fully saturated. The term “heterocyclic” thus includesheteroaryl groups as defined above as well as non-aromatic heterocyclicgroups. Preferably, a heterocyclic group is a 3- to 18-membered,particularly a 3- to 14-membered, especially a 5- to 10-membered, ringsystem containing at least one heteroatom selected from oxygen, sulphurand nitrogen atoms. Preferred heterocyclic groups include the specificheteroaryl groups named above as well as pyranyl, piperidinyl,pyrrolidinyl, dioxanyl, piperazinyl, morpholinyl, thiomorpholinyl,morpholinosulphonyl, tetrahydroisoquinolinyl and tetrahydrofuranylgroups.

A heterocyclylalkyl group may be any alkyl group substituted by aheterocyclic group. Preferably, the heterocyclic moiety is a 3- to18-membered, particularly a 3- to 14-membered, and especially a 5- to10-membered, heterocyclic group as defined above and the alkyl moiety isa C₁₋₆ alkyl, preferably C1-4 alkyl, and especially methyl, group.

An amino acid may be any α-amino acid, such as glycine, alanine, valine,leucine, isoleucine, serine, threonine, cysteine, cystine, methionine,aspartic acid, glutamic acid, aspargine, glutamine, lysine,hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan,proline, hydroxyproline or phenylglycine, and includes both D-andL-configurations. An amino acid ester may be any ester of such an aminoacid, alkyl esters, particularly C₁₋₄ alkyl esters, being especiallypreferred.

When any of the foregoing substituents are designated as beingoptionally substituted, the substituent groups which are optionallypresent may be any one or more of those customarily employed in thedevelopment of pharmaceutical compounds and/or the modification of suchcompounds to influence their structure/activity, stability,bioavailability or other property. Specific examples of suchsubstituents include, for example, halogen atoms, nitro, cyano,hydroxyl, cycloalkyl, alkyl, alkenyl, haloalkyl, alkoxy, haloalkoxy,amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl,alkanoyl, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonato,arylsulphinyl, arylsulphonyl, arylsulphonato, carbamoyl, alkylamido,aryl, heterocyclic and alkyl- or aryl-substituted heterocyclic groups.When any of the foregoing substituents represents or contains an alkylor alkenyl substituent group, this may be linear or branched and maycontain up to 12, preferably up to 6, and especially up to 4, carbonatoms. A cycloalkyl group may contain from 3 to 8, preferably from 3 to6, carbon atoms. An aryl group or moiety may contain from 6 to 10 carbonatoms, phenyl groups being especially preferred. A heterocyclic group ormoiety may be a 5- to 10-membered ring system as defined above. Ahalogen atom may be a fluorine, chlorine, bromine or iodine atom and anygroup which contains a halo moiety, such as a haloalkyl group, may thuscontain any one or more of these halogen atoms.

In one aspect, it is preferred, that R¹ represents a hydrogen atom, amethyl group, ethyl group or longer chain alkyl group or a branchedalkyl group containing up to 9 carbon atoms, preferably a hydrogen atom,a methyl group or an ethyl group.

In another preferred aspect, X represents a carbon atom, a sulfur atom,or a group PR³, P—O—R³ or P—N(R⁴)—R³ where R³ and R⁴ each independentlyrepresent a C₆₋₁₈ aryl group or a 5- to 10-membered C-linked heteroarylgroup or a 5- to 10-membered heterocyclyl-C₁₋₆ alkyl group optionallysubstituted by one or more substituents selected from the groupconsisting of halogen atoms, hydroxyl, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino and carboxyl groups. Preferably, X represents a carbon atomor a sulfur atom.

In a further preferred aspect, Z represents an oxygen atom, or a groupNR⁵ where R⁵ represents a hydrogen atom, a methyl group, ethyl group orlonger chain alkyl group or branched alkyl group containing up to 9carbon atoms, or a C₆₋₁₈ aryl group or a 5- to 10-membered C-linkedheteroaryl group or a 5- to 10-membered heterocyclyl-C₁₋₆ alkyl groupoptionally substituted by one or more substituents selected from thegroup consisting of halogen atoms, hydroxyl, C₁₋₄ alkyl, C₂₋₄ alkenyl,C1-4 haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino,di(C₁₋₄ alkyl)amino and carboxyl groups.

In another preferred aspect, R² represents a hydrogen atom or anoptionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl oraralkyl group, or a group OR⁶, SR⁶, NH₂, NHR⁶, or N(R⁶)₂ where each R⁶indepently represents a methyl group, ethyl group or longer chain alkylgroup or branched alkyl group containing up to 9 carbon atoms atoms, oris a C₆₋₁₈ aryl group or a 5- to 10-membered C-linked heteroaryl groupor a 5- to 10-membered heterocyclyl-C₁₋₆ alkyl group optionallysubstituted by one or more substituents selected from the groupconsisting of halogen atoms, hydroxyl, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, di(C₁₋₄alkyl)amino and carboxyl groups. Preferably, R² represents a group NH₂,or a group NHR⁶ where R⁶ represents an alkyl or aryl group, or a groupN(R⁶)₂ where R⁶ represent identical or differentiated alyl groups.

In a further preferred aspect, R¹ represents a hydrogen atom or anoptionally substituted allyl, alkenyl, alkynyl, cycloalkyl, aryl oraralkyl group, preferably a hydrogen atom or an alkyl group, morepreferably a hydrogen atom or a methyl group or an ethyl group; Xrepresents a carbon, phosphorus or sulfur atom, preferably a carbon orsulfuir atom; Z represents an oxygen atom or a group NR⁵ in where R⁵represents a hydrogen atom or an optionally substituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl or aralkyl group, preferably an oxygen atom;and R² represents a group OR⁶, SR⁶, NH₂, NHR⁶, or N(R⁶)₂ where each R⁶independently represents a hydrogen atom or an optionally substitutedalkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group, or a10α-dihydroartemisinyl group, preferably a hydrogen atom or anoptionally substituted alkyl or aryl group, more preferably R²represents a group NH₂, or a group NHR⁶ where R⁶ represents an alkylgroup, or a group N(R⁶)₂ where R⁶ represent identical or differentiatedalkyl groups.

In an especially preferred aspect, R¹ represents a hydrogen atom, Xrepresents a sulfoxide group S═O, Z represents an oxygen atom, and R²represents a group NH₂; or R¹ represents a hydrogen atom, X represents acarbon atom, Z represents a group NH, and R² represents a group NHR⁶where R⁶ represents a hydrogen atom or an optionally substituted alkyl,cycloalkyl, aryl or aralkyl group; or R¹ represents a hydrogen atom, Xrepresents a carbon atom, Z represents an oxygen atom, and R² representsa group NHR⁶ where R⁶ is a hydrogen atom or an optionally substitutedalkyl, cycloalkyl, aryl or aralkyl group.

It should also be appreciated that the compounds of general formula Iare capable of existing as different geometric and optical isomers. Thepresent invention thus includes both the individual isomers and mixturesof such isomers.

The present invention includes a compound of the general formula I asdefined above for use in the treatment and/or prophylaxis of a disease.Preferably, the disease is a disease caused by infection with aparasite. More preferably, the disease is a disease caused by infectionwith a parasite of the genus Plasmodium, the genus Neospora, or thegenus Eimeria.

The present invention also provides the use of a compound of the generalformula I as defined above for the manufacture of a medicament for thetreatment and/or prophylaxis of a disease caused by infection with aparasite. Preferably, the parasite is an organism of the genusPlasmodium, the genus Neospora, or the genus Eimeria.

The present invention also provides a process for the preparation of acompound of the general formula I which comprises reacting a compound ofthe general formula II

in which Y represents a group containing an oxygen atom attached to thecarbon atom of the artemisinin nucleus and also to a hydrogen atom ortrimethylsilyl group, with a suitable halogenating agent to form acompound of the general formula II in which Y represents a halogen atom;and, if desired, reacting the compound of general formula II thus formedwith an amine of the general formula R¹NHX(═Z)R² where R¹, R², X and Zare as defined above to form a compound of general formula I.

Suitable halogenating agents for forming compounds of the generalformula in which Y represents a halogen atom include diethylaminosulphurtrifluoride, chlorotrimethylsilane, bromotrimethylsilane andiodotrimethylsilane. In particular, compounds of the general formula IIin which Y represents a chlorine, bromine or iodine atom may be preparedby reacting a compound of the general formula II in which Y represents atrimethylsilyloxy group with a suitable chlorinating, brominating oriodinating agent respectively, such as chlorotrimethlysilane,bromotrimethylsilane or iodotrimethylsilane respectively. This reactionmay be conveniently carried out in the presence of a solvent. Suitablesolvents include aromatic solvents such as toluene, or halogenatedhydrocarbons, especially chlorinated hydrocarbons, such asdichloromethane. Preferably, the reaction is carried out at atemperature of −30 to +20° C., particularly −5 to +10° C., about 0° C.being especially preferred.

Compounds of the general formula II in which Y represents a fluorineatom may be conveniently prepared by reacting a compound of the generalformula II in which Y represents a hydroxyl group with a suitablefluorinating agent, such as diethylaminosulphur trifluoride. Thisreaction may be conveniently carried out in the presence of a solvent,suitable solvents including aromatic solvents such as toluene andhalogenated hydrocarbons, especially chlorinated hydrocarbons, such asdichloromethane. Preferably, the reaction is carried out at −5° C. toroom temperature, that is, −5 to +35° C., preferably 0 to 30° C. Thereaction may also be carried out under an inert atmosphere, such asnitrogen.

The reaction of an amine of the type R¹NHX(═Z)R² where R¹, R², X and Zare as defined above with a compound of the general formula II in whichY represents a halogen, preferably a chlorine or bromine, atom to form acompound of the general formula II in which Y represents the groupR¹NX(═Z)R² where R¹, R², X and Z are as defined above may beconveniently carried out in the presence of a solvent. Suitable solventsinclude halogenated hydrocarbons, especially chlorinated hydrocarbons,such as dichloromethane, and ethers, such as tetrahydrofuran.Preferably, the reaction is carried out at a temperature of −5 to +5°C., 0° C. being especially preferred.

When a compound of the general formula II in which Y represents abromine atom is to be further reacted with an amine to form a compoundof the general formula II in which Y represents a group R¹NHX(═Z)R²where R¹, R², X and Z are as defined above, it is preferred that thecompound of the general formula II in which Y represents a bromine atomis generated in situ by reacting a compound of the general formula II inwhich Y represents a trimethylsiloxy group with bromotrimethylsilane.

A compound of the general formula II in which Y represents atrimethylsiloxy group may be prepared by reacting dihydroartemisinin,that is, the compound of general formula II in which Y represents ahydroxyl group, with chlorotrimethylsilane in the presence of a base,such as pyridine or triethylamine. Preferably, the reaction is carriedout at room temperature, that is, 15 to 35° C., preferably 20 to 30° C.

Dihydroartemisinin, that is, the compound of general formula II in whichY represents a hydroxyl group, is a known compound and can be preparedby known processes.

The present invention also provides a pharmaceutical composition whichcomprises a carrier and, as active ingredient, a compound of the generalformula I as defined above.

A pharmaceutically acceptable carrier may be any material with which theactive ingredient is formulated to facilitate administration. A carriermay be a solid or a liquid, including a material which is normallygaseous but which has been compressed to form a liquid, and any of thecarriers normally used in formulating pharmaceutical compositions may beused. Preferably, compositions according to the present inventioncontain 0.5 to 95% by weight of active ingredient.

The compounds of general formula I can be formulated as, for example,tablets, capsules, suppositories or solutions. These formulations can beproduced by known methods using conventional solid carriers such as, forexample, lactose, starch or talcum or liquid carriers such as, forexample, water, fatty oils or liquid paraffins. Other carriers which maybe used include materials derived from animal or vegetable proteins,such as the gelatins, dextrins and soy, wheat and psyllium seedproteins; gums such as acacia, guar, agar, and xanthan; polysaccharides;alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins;synthetic polymers such as polyvinylpyrrolidone; polypeptide/protein orpolysaccharide complexes such as gelatin-acacia complexes; sugars suchas mannitol, dextrose, galactose and trehalose; cyclic sugars such ascyclodextrin; inorganic salts such as sodium phosphate, sodium chlorideand aluminium silicates; and amino acids having from 2 to 12 carbonatoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid,L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.

Auxiliary components such as tablet disintegrants, solubilisers,preservatives, antioxidants, surfactants, viscosity enhancers, colouringagents, flavouring agents, pH modifiers, sweeteners or taste-maskingagents may also be incorporated into the composition. Suitable colouringagents include red, black and yellow iron oxides and FD & C dyes such asFD & C blue No. 2 and FD & C red No. 40 available from Ellis & Everard.Suitable flavouring agents include mint, raspberry, liquorice, orange,lemon, grapefruit, caramel, vanilla, cherry and grape flavours andcombinations of these. Suitable pH modifiers include citric acid,tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.Suitable sweeteners include aspartame, acesulfame K and thaumatin.Suitable taste-masking agents include sodium bicarbonate, ion-exchangeresins, cyclodextrin inclusion compounds, adsorbates ormicroencapsulated actives.

For treatment of and prophylaxis against coccidiosis and relatedparasites, for instance, in poultry, especially in chickens, ducks,geese and turkeys, 0.1 to 100 ppm, preferably 0.5 to 100 ppm of theactive compound may be mixed into an appropriate, edible material, suchas nutritious food. If desired, the amounts applied can be increased,especially if the active compound is well tolerated by the recipient.Accordingly, the active compound can be applied with the drinking water.

For the treatment of a single animal, for instance, for the treatment ofcoccidiosis in mammals or toxoplasmosis, amounts of 0.5 to 100 mg/kgbody weight active compound are preferably administered daily to obtainthe desired results. Nevertheless, it may be necessary from time to timeto depart from the amounts mentioned above, depending on the body weightof the experimental animal, the method of application, the animalspecies and its individual reaction to the drug or the kind offormulation or the time or interval in which the drug is applied. Inspecial cases, it may be sufficient to use less than the minimum amountgiven above, whilst in other cases the maximum dose may have to beexceeded. For a larger dose, it may be advisable to divide the dose intoseveral smaller single doses.

The present invention also includes a pharmaceutical composition asdescribed above for use in the treatment and/or prophylaxis of a diseasecaused by infection with a parasite. Preferably, the parasite is anorganism of the genus Plasmodium, the genus Neospora, or the genusEimeria.

The present invention also provides a method for treating a diseasecaused by infection with a parasite which comprises administering to ahost in need of such treatment a therapeutically effective amount of acompound of the general formula I as defined above. Preferably, theparasite is an organism of the genus Plasmodium, the genus Neospora, orthe genus Eimeria.

The present invention is further illustrated by the following examples.

EXAMPLES Example 1 10α-(Sulfamino)dihydroartemisinin

(Formula I: R¹═H; X S═O; Z=O; R²═NH₂)

Trimethylsilyl bromide (0.16 g, 0.14 ml, 1.05 mmol) was added dropwiseto a cold (0° C.) stirred solution of10α-(trimethylsiloxy)dihydroartemisinin (356 mg, 1.0 mmol) indichloromethane (5 ml). After 15 min. (tlc), a solution of sulfamide(0.19 g, 2.0 inmol) in THF (6 ml) was added. After 1.5 h, the reactionwas quenched with saturated NaHCO_(3(aq)) (10 ml) and extracted withdiethyl ether (3×10 ml). The organic extracts were combined and dried(MgSO₄). Filtration and evaporation of filtrate gave a dark green solidwhich was purified by column chromatography on silica with ethylacetate-hexanes (40:60) as eluent. Pooling and evaporation ofappropriate fractions gave a white powder (211.48 mg, 57%). M.p.168-168.7° C. (decomposed); [α]_(D) ²²+16.76° (c 0.68 MeOH); IR (KBr)ν_(max) 3387, 3226, 2959, 2934, 2880, 1631, 1456, 1375, 1323, 1308,1147, 1128, 1024; ¹H-NMR: δ_(H) 7.79 (1H, d, NH, J=8.63 Hz), 6.44 (2H,s, NH₂), 5.37 (1H, s, H-12), 4.58 (1H, pseudo-triplet, H-10, J=9.23 Hz),2.31-2.12 (2H, m), 2.00-1.96 (1H, m), 1.82-1.77 (1H, m), 1.64-1.61 (2H,m), 1.51-1.31 (4H, m), 1.28 (3H,s 3-Me), 1.20-1.12 (1H, m), 1.10-0.94(1H, m), 0.89 (3H, d, 9-Me, J=6.23 Hz), 0.78 (3H, d, 6-Me, J=7.11 Hz;¹³C-NMR: δ_(c)103.31, 90.61, 80.47, 79.98, 51.36, 45.14, 36.34, 36.01,33.66, 31.56 25.66, 24.57, 21.24, 20.46, 13.60MS (CI, CH₄) m/z 363 (MH⁺,7%), 364 (MH⁺, ¹³C, 1%); Analysis calculated for C₁₅H₂₆N₂O₆S requires C,49.71; H, 7.23; found C, 49.59; H, 7.29; N, 7.58

Example 2 Bis[(10α-dihydroartemisinyl)]sulfamide

(Formula I: R¹═H; X═SO; Z═O; R²═NH(10α-dihydroartemisinyl))

Trimethylsilyl chloride (0.42 g, 0.49 ml, 3.87 mmol) was added to a cold(0° C.) stirred mixture of dihydroartemisinin (0.5 g, 1.76 inmol) andsodium bromide (199 mg, 1.94 mmol) in toluene (2 ml). After 1 h (tlc), asolution of sulfamide (85 mg, 0.88 mmol) in THF (2 ml) was addedrapidly. After 3.5 h, water (5 ml) followed by diethyl ether (10 ml)were added. The aqueous layer was separated and extracted further withdiethly ether (3×5 ml). The organic extracts were combined and dried(MgSO4). Filtration and evaporation of filtrate gave a dark green glassysolid which was purified by column chromatography on silica using ethylacetate-hexanes (25:75) as eluent. Pooling and evaporation ofappropriate fractions gave a pale yellow powder (178.9 mg, 32%). M.p.183-184° C. (decomposed); IR (KBr) ν_(max) 3035, 3216, 2927, 2875, 1458,1381, 1348, 1167, 1149, 1130, 1113, 1024, 916, 876, 735; ¹H-NMR: δ_(H)5.42 (2H, broad-doublet, 2×NH, J=11.2 Hz), 5.35 (2H, s, 2×H-12), 4.81(2H, pseudo-triplet, 2×H-10, J=10.4 Hz), 2.36-2.29 (4H, m), 2.03-2.00(2H, m), 1.89-1.86 (2H, m), 1.76-1.70 (4H, m), 1.57-1.54 (2H, m), 1.45(6H, s, 2×3-Me), 1.44-b 1.42 (2H, m), 1.38-1.77 (6H, m), 1.02-0.97 (2H,m), 0.95(6H, d, 2×9-Me, J=6.4 Hz), 0.91 (6H, d, 2×6-Me, J=6.8 Hz);¹³C-NMR: δ_(c) 104.32, 91.06, 82.80, 79.50, 51.68, 45.67, 37.30, 36.31,34.09, 32.46, 25.71, 24.80, 21.55, 20.28, 13.42,

1. A compound of the formula I:

or a salt thereof, or a solvate thereof, or a solvate of a salt thereof,in which R¹ represents a hydrogen atom or an optionally substitutedalkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group; X representsa carbon atom, a sulfur atom, a sulfoxide group S═O or a group PR³,P—O—R³ or P—N(R⁴)—R³ where R³ and R⁴ each independently represent ahydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl,cycloalkyl, aryl or aralkyl group; Z represents an oxygen atom, a sulfuratom or a group NR⁵ where R⁵ represents a hydrogen atom or an optionallysubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group;and R² represents a hydrogen atom or an optionally substituted alkyl,alkenyl, alkynyl, cycloalkyl, aryl or aralky group, or a group N(R⁶)₂,NHNH₂, NR⁶NHR⁶ or NR⁶N(R⁶)₂, or a group OR⁶ or SR⁶ where each R⁶independently represents a hydrogen atom or an optionally substitutedalkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group, or a10α-dihydroartemisinyl group, or R² represents a group OR⁷ or NR⁶R⁷where R⁶ represents a group as defined above and R⁷ represents a bondattached as a substituent to R⁵ together with the group —X═Z- forming anoptionally substituted heterocyclic group where Z represents a groupNR⁵, or R⁷ represents a bond attached as a substituent to R¹ togetherwith the group —N—X(═Z)- forming an optionally substituted heterocyclicgroup.
 2. A compound according to claim 1 in which R¹ represents ahydrogen atom, a methyl group, ethyl group or longer straight-chainalkyl group or a branched alkyl group containing up to 9 carbon atoms.3. A compound according to claim 1 in which X represents a carbon atom,a sulfur atom, or a group PR³, P—O—R³ or P—N(R⁴)—R³ where R³ and R⁴ eachindependently represent a C₆₋₁₈ aryl group or a 5- to 10-memberedC-linked heteroaryl group or a 5- to 10-membered heterocyclyl-C₁₋₆ alkylgroup optionally substituted by one or more substituents selected fromthe group consisting of halogen atoms, hydroxyl, C₁₋₄ alkyl, C₂₋₄alkenyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino and carboxyl groups.
 4. A compoundaccording to claim 1 in which Z represents an oxygen atom, or a groupNR⁵ where R⁵ represents a hydrogen atom, a methyl group, ethyl group orlonger straight-chain alkyl group or branched alkyl group containing upto 9 carbon atoms or a C₆₋₁₈ aryl group or a 5- to 10-membered C-linkedheteroaryl group or a 5- to 10-membered heterocyclyl-C₁₋₆ alkyl groupoptionally substituted by one or more substituents selected from thegroup consisting of halogen atoms, hydroxyl, C₁₋₄ alkyl, C₂₋₄, alkenyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino,di(C₁₋₄ alkyl)amino and carboxyl groups.
 5. A compound according toclaim 1 in which R² represents a hydrogen atom or an optionallysubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group,or a group OR⁶, SR⁶, NH₂, NHR⁶, or N(R⁶)₂ where each R⁶ independentlyrepresents a methyl group, ethyl group or longer straight-chain alkylgroup or branched alkyl group containing up to 9 carbon atoms, or is aC₆₋₁₈ aryl group or a 5- to 10-membered C-linked heteroaryl group or a5- to 10-membered heterocyclyl-C₁₋₆ alkyl group optionally substitutedby one or more substituents selected from the group consisting ofhalogen atoms, hydroxyl, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino andcarboxyl groups.
 6. A compound according to claim 1 in which R¹represents a hydrogen atom or an optionally substituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl or aralkyl group; X represents a carbon,phosphorus or sulfur atom; Z represents an oxygen atom or a group NR⁵ inwhere R⁵ represents a hydrogen atom or an optionally substituted alkyl,alkenyl, alkynyl, cycloalkyl, aryl or aralkyl group; and R² represents agroup OR⁶, SR⁶, NH₂, NHR⁶, or NH², or N(R⁶)₂ where each R⁶ independentlyrepresents a hydrogen atom or an optionally substituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl or aralkyl group, or a 10α-dihydroartemisinylgroup.
 7. A compound according to claim 1 in which R¹ represents ahydrogen atom, X represents a sulfoxide group S═O, Z represents anoxygen atom, and R² represents a group NH₂, or in which R¹ represents ahydrogen atom, X represents a carbon atom, Z represents a group NH, andR² represents a group NHR⁶ where R⁶ represents a hydrogen atom or anoptionally substituted alkyl, cycloalkyl, aryl or aralkyl group; or inwhich R¹ represents a hydrogen atom, X represents a carbon atom, Zrepresents an oxygen atom, and R² represents a group NHR⁶ where R⁶ is ahydrogen atom or an optionally substituted alkyl, cycloalkyl, aryl oraralkyl group.
 8. A process for the preparation of a compound of thegeneral formula I according to claim 1 which comprises reacting acompound of the formula II comprising an atremisinin nucleus:

in which Y represents a group comprising an oxygen atom attached to thecarbon atom of the artemisinin nucleus and also to a hydrogen atom ortrimethylsiyl group, with a suitable halogenating agent to form acompound of the formula II in which Y represents a halogen atom; and, ifdesired, reacting the compound of formula II in which Y represents ahalogen atom with an amine of the formula:R¹NHX(═Z)R² where R¹, R², X and Z are as defined in claim 1 to form acompound of the formula I.
 9. (canceled.)
 10. A pharmaceuticalcomposition which comprises a carrier and a therapeutically effectiveamount of a compound according to claim
 1. 11. (canceled.) 12.(canceled.)
 13. A method for treating a disease caused by infection witha parasite which comprises administering to a host in need of suchtreatment a therapeutically effective amount of a compound according toclaim
 1. 14. A compound according to claim 2 in which R¹ represents ahydrogen atom, a methyl group or an ethyl group.
 15. A compoundaccording to claim 6 in which R¹ represents a hydrogen atom or an alkylgroup; X represents a carbon or sulfur atom; Z represents an oxygenatom; R6 represents a hydrogen atom or an optionally substituted alkylor aryl group; or R² represents a group NH₂, or a group NHR⁶ where R⁶represents an alkyl group, or a group N(R⁶)₂ where R⁶ representsidentical or different alkyl groups.
 16. A compound according to claim15 in which R¹ represents a hydrogen atom or a methyl group or an ethylgroup; or R² represents a group NH₂, or a group NHR⁶ where R⁶ representsan alkyl group, or a group N(R⁶)₂ where R⁶ represents identical ordifferent alkyl groups.